Biology subjects

Mellios, N.

Publications and source records attributed to Mellios, N..

4 recordsLinked to original sources

bioRxiv2026

Unraveling a comparative landscape of protein-coding genes linked to neuroimmune function during adulthood consequent of prenatal alcohol exposure

BackgroundAn overwhelming body of evidence suggests neuroimmune dysfunction as a key underlying mechanism of FASD-associated adverse CNS outcomes. While few studies have highlighted the lingering effects of prenatal alcohol exposure (PAE) on producing specific immune factors, others suggest a primed neuroimmune state in adulthood, in which a proinflammatory bias is unmasked following subsequent immune activation in later-life. However, the PAE-induced neuroimmune landscape in adulthood remains poorly defined. We hypothesized that PAE induces long-term changes in gene expression linked to neuroimmune function that may be brain region-specific. MethodsUsing long-read next-generation RNA sequencing of brain tissues from a previously established model of a moderate PAE in mice, we compared across six regions: medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hypothalamus, hippocampus, midbrain, and medulla. A comprehensive bioinformatics analysis investigated PAE-induced changes, dysregulated gene pathways, and transcriptional regulators with a focus on neuroimmune function. ResultsOur data identified at least 60 differentially expressed genes per brain region, many of which were associated with neuroimmune function. Upregulation of multiple proinflammatory factors and pathways was observed, suggesting ongoing baseline neuroimmune activation, potentially involving PXR, TNF, TLR4, the complement pathway, and various cytokine and chemokine signaling. A comparative analysis identified multiple upstream transcriptional regulators across multiple brain regions, including MECP2, TCF7L2, and IL-4. Importantly, this unbiased analysis revealed heterogeneity across brain regions in the activation of canonical immune pathways and highlighted previously unprecedented roles of pathways such as PXR, matrix metalloproteases, and cytokine signaling (e.g., IL-15, IL-27, IL-17) in PAE. ConclusionsPAE creates a unique inflammatory signature in the adult brain, even in the absence of secondary injury, with novel patterns of region-specific changes in genes implicated in glial-immune function. These data identified potential immune targets to elucidate the mechanisms underlying behavioral dysfunction and provide a framework for future therapeutic interventions.

neuroscience↗

bioRxiv2024

The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex

Circular RNAs (circRNAs) are a class of closed-loop, single stranded RNAs whose expression is particularly enriched in the brain. Despite this enrichment and evidence that the expression of circRNAs are altered by synaptic development and in response to synaptic plasticity in vitro, the regulation by and function of the majority of circRNAs in experience-dependent plasticity in vivo remain unexplored. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of experience-dependent developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent mRNA forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following 3-day MD. Knockdown of circHomer1 delayed the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown also led to a reduction in average dendritic spine size prior to MD but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 knockdown impairs experience-dependent AMPA receptor endocytosis. Thus, the expression of multiple circRNAs are regulated by experience-dependent developmental plasticity, and our findings highlight the essential role of circHomer1 in V1 synaptic development and experience-dependent plasticity. Significance StatementCircular RNAs (circRNAs) are a class of closed-loop RNAs formed through back-splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in experience-dependent plasticity remains poorly understood. We conducted an in vivo transcriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in the mouse visual cortex and highlight circHomer1, a circRNA derived from the Homer1 gene, as a circRNA critical for synaptic development and experience-dependent plasticity in vivo.

neuroscience↗

bioRxiv2024

A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the "trial and error" approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.

neuroscience↗

bioRxiv2020

Astrocytic glutamate uptake coordinates experience-dependent, eye-specific refinement in developing visual cortex

The uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two-photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye-specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye-specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, the balance of excitation and inhibition in cortical circuits is dysregulated with an increase in somatostatin positive interneurons, decrease in parvalbumin positive interneurons, and increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience-dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex. SIGNIFICANCEWe show that astrocytic glutamate uptake via the transporter GLT1 is necessary for activity-dependent regulation of cortical inputs. Dysregulation of GLT1 expression and function leads to a disruption of binocular refinement and matching in visual cortex. Inputs from the ipsilateral eye are stronger, and monocular deprivation, which upregulates GLT1 expression in a homeostatic fashion, causes a paradoxical reduction of ipsilateral, non-deprived eye, responses. These results provide new evidence for the importance of glutamate transport in cortical development, function, and plasticity.

neuroscience↗